We studied the role of Nitric Oxide (NO) in Cyclosporine A (CsA)-induced hypertension to understand the relationship by which various vasoactive substances produce their effects, with special attention to NO. The effect of CsA on vascular responses was determined in Sprague-Dawley rats and in isolated rat aortic rings that were either intact or denuded of endothelium. We found that 1. CsA administration to rats increased mean arterial pressure and concomitantly decreased levels of both nitrate/nitrite, metabolites of NO, and guanosine 3', 5'-cyclic monophosphate, which mediates NO action, in the urine; 2. With endothelin (ET) as our model vasoconstrictor, ET-induced tension was increased in aortic rings from CsA-treated rats compared to controls and was the same as that of normal rings denuded of endothelium; 3. Aortic rings from CsA-treated rats did not relax in response to acetylcholine, and 4. All the effects of CsA, both in vivo and in vitro, were reversed by daily ip injections of L-Arg (substrate for NO synthase). We are studying the mechanism involved in CsA-induced hypertension.